1. Field of the Invention
The present invention relates to chiral ligands and transition metal complexes thereof that are useful in asymmetric reactions. More particularly, the present invention relates to chiral phospholanes, P,N ligands, N,N ligands, biphenols, and chelating phosphines and transition metal complexes thereof that are useful in asymmetric catalysis.
2. Description of the Prior Art
Discovery of new chiral ligands has been an essential element in the development of highly enantioselective transition metal-catalyzed reactions. New structural motifs play an important role in dictating enantioselectivities and reactivities of a reaction. With the growing demand of enantiomerically pure compounds in pharmaceutical and agrochemical industry, asymmetric catalysis has become increasingly more important because of its high efficiency.
For example, biaryl atropisomeric ligands have been explored as effective ligand scaffolds for many asymmetric transformations. One of the most frequently used chiral chelating phosphines is BINAP (Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345, Ohkuma, T.; Koizumi, M.; Doucet, H.; Pham, T.; Kozawa, M.; Murata, K.; Katayama, E.; Yokozawa, T.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1998, 120, 13529.).
Another family of excellent chiral phosphines is so called DuPhos (Burk, U.S. Pat. No. 5,329,015, U.S. Pat. Nos. 5,202,493, 5,329,015, Burk, M, J. J. Am. Chem. Soc. 1991, 113, 8518, Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am. Chem. Soc. 1993, 115, 10125. Burk, M. J.; Wang, Y. M.; Lee, J. R. J. Am. Chem. Soc. 1996, 118, 5142), which has a rigid 1, 2-bis(phosphino)benzene backbone and electron-donating phospholane groups.
Gladiali et al. (Gladiali, S.; Dore, A.; Fabbri, D.; Lucchi, O. D.; Manassero, M. Tetrahedron Asymmetry, 1994, 511.) made monodentate chiral phospholanes bearing the 1, 1xe2x80x2-binaphthyl framework. However the method for their synthesis is not feasible to make the corresponding chelating chiral phospholanes. Stelzer et al. (Bitterer, F.; Herd, O.; Kuhnel, M.; Stelzer, O.; Weferling, N.; Sheldrick, W. S.; Hahu, J.; Nagel, S.; Rosch, N. Inorg. Chem. 1998, 37, 6408) only made racemic chelating phospholanes.
Reetz et al. prepared chelating chiral phosphinites using readily accessible binaphthanols as starting materials and demonstrated that they are excellent ligands for Rh-catalyzed asymmetric hydrogenation of dehydroaminoacids (Reetz, M. T.; Gosberg, A.; Goddard, R.; Kyung, S. J. Chem. Soc., Chem. Commun. 1998, 2077). John Brown made a chiral phosphine and pyridine ligand with a biaryl chirality. Several related chiral ligands are shown in the Figure below. 
While these ligands have been useful in a number of asymmetric reactions, there are still many more asymmetric transformations that can benefit from the discovery of new chiral ligands.
The present invention includes a ligand selected from the group consisting of compounds represented by A through K: 
herein the bridge group is selected from the group consisting of: (CH2)n wherein n is an integer ranging from 1 to 8, (CH2)nW(CH2)m wherein n and m are independently an integer ranging from 1 to 8 and W, wherein W is a divalent group selected from the group consisting of: 1,2-divalent phenyl, 2,2xe2x80x2-divalent 1,1xe2x80x2-biphenyl, 2,2xe2x80x2-divalent-1,1xe2x80x2-binaphthyl, ferrocene, and a substituted derivative thereof; wherein each substituent in said substituted derivative is selected from the group consisting of: aryl, alkyl having 1-8 carbon atoms, F, Cl, Br, I, COOR, SO3R, PR3R2, OR, SR, PR2, AsR2, SbR2, aryloxyl, nitro, NR2, vinyl, substituted vinyl and a combination thereof, wherein each R is independently selected from the group consisting of: hydrogen, alkyl, aryl, alkaryl and aralkyl; wherein each X is independently selected from the group consisting of: hydrogen, halide, alkyl, aryl, alkoxy, silane, carboxylate and amide; each Y is independently selected from the group consisting of: hydrogen, alkyl, aryl, alkoxy, carboxylate and amide; and each Z is independently selected from the group consisting of: hydrogen, alkyl, aryl, alkoxy, amide, carboxylate, and a heterocyclic compound.
The present invention further includes a catalyst prepared by a process comprising contacting a transition metal salt, or a complex thereof, and a ligand selected from the group consisting of compounds represented by A through K as described above.
The present invention still further includes a process for preparation of an asymmetric compound using a catalyst according to the present invention. The process comprises contacting a substrate capable of forming an asymmetric product by an asymmetric reaction and a catalyst prepared by a process comprising contacting a transition metal salt, or a complex thereof, and a ligand selected from compounds represented by A through K as described above.
The ferrocene-based irridium (R,R)-f-binaphane complex reduces imines to the corresponding amines with 95-99.6% enantioselectivity and reduces xcex2-substituted-xcex1-arylenamides with 95% enantioselectivity.
The present invention includes new phospholane ligands with mixed biaryl chirality. The P,N ligands, N,N ligands, biphenols and chelating phosphines are also derivatives of biaryl atropisomers. Also included are chiral five-membered ring phospholanes with stereogenic centers in 3,4 positions, phospholanes with a chiral biaryl atropisomer as the backbone and atropisomers of P,N ligands, N,N ligands, biphenols and chelating bisphophines. These chiral ligands can be used to facilitate a variety of metal-catalyzed asymmetric transformations. The bridge group can be (CH2)n wherein n is an integer ranging from 1 to 8, (CH2)nW(CH2)m wherein n and m are independently an integer ranging from 1 to 8 and W, wherein W is a divalent group selected from the group consisting of: 1,2-divalent phenyl, 2,2xe2x80x2-divalent 1,1xe2x80x2-biphenyl, 2,2xe2x80x2-divalent-1,1xe2x80x2-binaphthyl, ferrocene, and a substituted derivative thereof. Each substituent in the substituted derivative can be aryl, alkyl having 1-8 carbon atoms, F, Cl, Br, I, COOR, SO3R, PR3R2, OR, SR, PR2, AsR2, SbR2, aryloxyl, nitro, NR2, vinyl, substituted vinyl and a combination thereof and each R can independently be hydrogen, alkyl, aryl, alkaryl and aralkyl. Each X can independently be hydrogen, halide, alkyl, aryl, alkoxy, silane, carboxylate and amide, each Y can independently be hydrogen, alkyl, aryl, alkoxy, carboxylate and amide and each Z can independently be hydrogen, alkyl, aryl, alkoxy, amide, carboxylate, and a heterocyclic compound (i.e., a nitrogen, sulfur or oxygen heterocycle).
For each class of A to K ligands, the corresponding enantiomer, as well as enantiomeric mixtures, are also contemplated. A and B ligands are chelating chiral phospholanes with biaryl chirality in their backbone. C ligands have five-membered ring phospholanes with stereogenic centers in 3,4 positions. D and E are chiral P,N ligands with biaryl chirality. F and G are chiral N,N ligands with biaryl chirality. H and I are chiral biphenols with biaryl chirality. J and K are chiral phosphines with biaryl chirality. The preferred ligands of the present invention are selected from ligands designated A through K, which include members represented by the formula L1 through L56 depicted below: 
L1 to L8 are examples of A ligands. L9 to L16 are examples of B ligands. L17 to L24 are examples of C ligands. L25 to L35 are examples of D and E ligands. L36 to L44 are examples of F and G ligands. L45 to L50 are examples of F and G ligands. L51 to L56 are examples of J and K ligands.
f-Binaphane ligand and transition metal complexes thereof are preferred, irridium complexes of f-binaphane being the most preferred. The unsubstituted (R,R)-f-binaphane ligand is represented by the formula: 
The highest enantioselectivity ( greater than 99%ee) has been achieved in the asymmetric hydrogenation of imines using Ir-f-binaphane complex as the catalyst.
The preparation of L1, L5, L17, L25, L36, L45, L51 and (R,R)-binaphane are illustrated below. Other members of L1 to L56 ligands can be prepared by similar procedures. 
The ligand according to the present invention can be racemic, i.e., racemic mixture of enantiomers, or a non-racemic mixture of enantiomers. Preferably, the ligand according to the present invention is one of the enantiomers. When the ligand is a non-racemic mixture of enantiomers, preferably it has an optical purity of at least 85%ee, more preferably, it has an optical purity of at least 95%ee.
According to the above reaction scheme, (R,R)-1,2-bis{(R)-4,5-dihydro-3H-dinaphtho[2,1-c:1xe2x80x2,2xe2x80x2-e]phosphenino}benzene, abbreviated as (R,R)-binaphane, has been prepared in high yield and high optical purity. This chiral chelating phosphine has a rigid 1,2-bis(phosphino)benzene backbone and has both binaphthyl chirality and a phospholane functionality.
The preparation procedure is illustrated below: 
As illustrated schematically above, (R,R)-binaphane was prepared employing a practical synthesis route based on readily accessible starting materials. Enanatiomerically pure binaphthol can be easily obtained using a classic resolution procedure (Cai, D.; Hughes, D. L.; Verhoever, T. R.; Reider, P. J. Tetrahedron Letter, 1995, 7991). (R)-2,2xe2x80x2-bistriflate-1,1xe2x80x2-binaphthyl (2) was made from (R)-binaphthol by treating with excess triflic anhydride and pyridine in CH2Cl2. Kumada coupling of bistriflate (2) with methyl magnesium bromide gave (R)-2,2xe2x80x2dimethyl-1,1xe2x80x2-binaphthyl (3) in high yield. (R)-2,2xe2x80x2-Dibromomethyl-1,1xe2x80x2-binaphthyl (4) was prepared by bromination of 3 with NBS. A simple anion exchange of (R)-2,2xe2x80x2-dibromomethyl-1,1xe2x80x2-binaphthyl (4) with LiCl afforded (R)-2,2xe2x80x2-dichloromethyl-1,1xe2x80x2-binaphthyl (5) in high yield. A key element of our synthesis of chelating phospholane such as binaphane is utilization of a less reactive (R)-2,2xe2x80x2-dichloromethyl-1,1xe2x80x2-binaphthyl (5) to avoid the intermolecular reaction with phosphine anions which existed when using a more reactive (R)-2,2xe2x80x2-dibromomethyl-1,1xe2x80x2-binaphthyl (4). Refluxing (R)-2,2xe2x80x2-dichloromethyl-1,1xe2x80x2-binaphthyl (5) with 1,2-bis(phosphino)benzene and NaH in THF followed by recrystallization from ether gave (R,R)-binaphane in 55% yield. This efficient synthesis allows us to make binaphane in a large scale. Using this procedure, we have also made the corresponding monodentate chiral binaphthyl phospholane from phenylphosphine in  greater than 90% yield.
In a similar connectivity as in binaphane, new chiral five-membered ring chelating phospholanes with stereogenic centers in 3,4 positions can be effective. An important transformation in making the binaphthyl phospholane ligand is Kumada coupling of ArOTf with RMgBr (from 2 to 3). Stille and Suzuki coupling may also work as well. Based on these coupling strategies, a series of new atropisomers of P,N ligands, N,N ligands, biphenols and chelating bisphophines can be derived.
Chiral f-binaphane (or a substituted derivative thereof) was prepared according to a process comprising contacting chiral 1,1xe2x80x2-di(chloromethyl)binaphthyl (or a substituted derivative thereof) and 1,1xe2x80x2-bisphosphinoferrocene (or a substituted derivative thereof) in the presence of a base and a solvent to produce f-binaphane (or the substituted derivative thereof). Preferably, the base is NaH and the solvent is tetrahydrofuran is (THF).
The present invention also includes a catalyst prepared by a process comprising contacting a transition metal salt, or a complex thereof, and a ligand selected from the group consisting of compounds represented by A through K.
As for the ligand, the catalyst according to the present invention can be racemic, such as, a racemic mixture of enantiomers, or it can be a non-racemic mixture of enantiomers. Preferably, the catalyst according to the present invention is one of the enantiomers. When the ligand according to the present invention is a non-racemic mixture of enantiomers, preferably it has an optical purity of at least 85%ee, more preferably, it has an optical purity of at least 95%ee.
Suitable transition metals for the preparation of the catalyst include Pt, Pd, Rh, Ru, Ir, Cu, Ni, Mo, Ti, V, Re and Mn.
The catalyst can be prepared by contacting a transition metal salt or its complex and a ligand selected from A through K. The transition metal salt or complex can be PtCl2; Pd2(DBA)3; Pd(OAc)2; PdCl2(RCN)2; [Pd(allyl)Cl]2; [Rh(COD)Cl]2; [Rh(COD)2]X; Rh(acac) (CO)2; Rh(ethylene)2(acac); Rh(CO)2Cl2; Ru(RCOO)2(diphosphine); Ru(methylallyl)2(diphosphine); Ru(aryl group)X2(diphosphine); RuCl2(COD); [Rh(COD)2]X; RuX2(diphosphine); RuCl2(xe2x95x90CHR) (PRxe2x80x23)2; Ru(ArH)Cl2; Ru(COD) (methylallyl)2; [Ir(COD)2Cl]2; [Ir(COD)2]X; Cu(OTf); Cu(OTf)2; Cu(Ar)X; CuX; NiX2; Ni(COD)2; MoO2(acac)2; Ti(OiPr)4; VO(acac)2; MeReO3; MnX2 or Mn(acac)2; wherein each R and Rxe2x80x2 can independently be alkyl or aryl; Ar is an aryl group; and X is a counteranion. The preferred counteranions include halogen, BF4, ClO4, SbF6, CF3SO3 and a mixture thereof.
The catalyst may be prepared in situ or as an isolated compound. An example of the preferred catalyst of the present invention is chiral Ir-f-binaphane catalyst.
In another aspect, the present invention includes a process for preparation of an asymmetric compounds using the catalysts described above. The process includes the step of contacting a substrate capable of forming an asymmetric product by an asymmetric reaction and a catalyst prepared by contacting a transition metal salt, or a complex thereof, and a ligand selected from ligands represented by A through K.
Suitable asymmetric reactions is include hydrogenation, hydride transfer, hydrosilylation, hydroboration, hydrovinylation, hydroformylation, allylic alkylation, cyclopropanation, Diels-Alder reaction, Heck reaction, isomerization, Aldol reaction, Michael addition and epoxidation. Preferably, the asymmetric reaction is hydrogenation and the substrate to be hydrogenated is an ethylenically unsaturated compound, imine, ketone, enamine, enamide, and vinyl ester. Suitable catalysts for the hydrogenation of imines to produce a chiral amine include Ir complex of chiral f-binaphane and Rh complex of chiral binaphane.
To test synthetic utility of (R,R)-binaphane, asymmetric hydrogenation of enamides using a Rh-(R,R)-binaphane complex as the catalyst was conducted. The imine reduction may be carried out in the presence of additional catalysts, such as iodine or H+.
Initially, several experiments were performed to screen optimal conditions for hydrogenation of N-acetyl-phenylethenamine. Rh(COD)2PF6 was found as a better catalyst precursor compared with a neutral Rh species [Rh(COD)Cl]2. Increase of H2 pressure results in decrease of enantioselectivity of the asymmetric hydrogenation. For example, 85%ee was obtained under 300 psi H2 while 90%ee was achieved under 20 psi H2. Variation of solvents causes dramatic changes in both enantioselectivity and reactivity. While hydrogenation was complete in CH2Cl2 with 90%ee, both reactivity and enantioselectivity were lower in methanol (14%ee and 86% conversion).
Several enamides were prepared according to literature procedures and were used as substrates for the asymmetric hydrogenation reaction. Table 1 lists results obtained under the optimal conditions for hydrogenation of N-acetyl-phenylethenamine (6a). Although very good enantioselectivity has been obtained for hydrogenation of xcex1-arylenamides without substitituents in the xcex2-position, the highlight of the Rh-binaphane catalyst is its ability to reduce xcex2-substituted-xcex1-arylenamides with excellent enantioselectivities. Several xcex2-substituted-xcex1-arylenamides with the mixture of (E)/(Z) isomers were reduced in high enantioselectivities (entries 7-13, 95%-99.6%ee). A small electronic effect was observed. These enantioselectivities with the Rh-(R,R)-binaphane catalyst is the highest reported to date. Since the product 7 can be easily converted to the corresponding arylalkylamine through hydrolysis under acidic condition, hydrogenation with the Rh-binaphane complex provides a practical method for preparing a variety of chiral arylalkylamines.